N-heterocyclic derivatives as NOS inhibitors

ABSTRACT

N-Heterocyclic derivatives of the following formula:  
                 
 
where m, n, p, A 1 , R 1 , R 2 , R 3  and R 4  are described herein, as well as other N-heterocyclic derivatives, are useful as inhibitors of nitric oxide synthase. Pharmaceutical compositions containing these compounds, methods of using these compounds as inhibitors of nitric oxide synthase and processes for synthesizing these compounds are also described herein.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/377,274, filed Apr. 30, 2002, which is incorporated herein infull by reference.

FIELD OF THE INVENTION

The invention relates to a series of N-heterocyclic compounds andderivatives useful as inhibitors of nitric oxide synthase (NOS) and tomethods of therapy for various diseases employing those compounds.

BACKGROUND OF THE INVENTION

Nitrogen monoxide (NO) has been implicated in a number of diversephysiological processes, including smooth muscle relaxation, plateletinhibition, nerve transmission, immune regulation and penile erection.Nitric oxide is produced under various conditions by virtually allnucleated mammalian cells. A number of pathologies are ascribed toabnormalities in NO production including stroke, insulin dependentdiabetes, septic shock-induced hypotension, rheumatoid arthritis andmultiple sclerosis. Nitric oxide is synthesized in biological tissues byan enzyme called nitric oxide synthase (NOS) which uses NADPH andmolecular oxygen to oxidize L-arginine to citrulline and nitric oxide.

Nitric oxide synthase (NOS) exists in at least three isoforms, whichfall into two primary categories: constitutive and inducible. Twoconstitutive isoforms, which are calcium and calmodulin dependent, havebeen identified, and one inducible isoform has been identified. Theconstitutive isoforms are (1) a neuronal isoform, NOS-1 or nNOS, whichis found in the brain and skeletal muscles and (2) an endothelialisoform, NOS-3 or eNOS, which is expressed in the endothelium of bloodvessels, the epithelium of the bronchial tree and in the brain. Theseconstitutive isoforms are not the target of the NOS inhibitors of thepresent invention.

The inducible isoform (NOS2 or iNOS) is expressed in virtually allnucleated mammalian cells following exposure to inflammatory cytokinesor lipopolysaccharide. Its presence in macrophages and lung epithelialcells is particularly noteworthy. The inducible isoform is neitherstimulated by calcium nor blocked by calmodulin antagonists. It containsseveral tightly bound co-factors, including FMN, FAD andtetrahydrobiopterin.

Nitric oxide generated by the inducible form of NOS has been implicatedin the pathogenesis of inflammatory diseases. In experimental animals,hypotension induced by lipopolysaccharide or tumor necrosis factor a canbe reversed by NOS inhibitors. Conditions which lead to cytokine-inducedhypotension include septic shock, hemodialysis and interleukin therapyin cancer patients. It is expected that an iNOS inhibitor would beeffective in treating cytokine-induced hypotension. In addition, recentstudies have suggested a role for NO in the pathogenesis ofinflammation, and NOS inhibitors would therefore have beneficial effectson inflammatory bowel disease, cerebral ischemia and arthritis.Inhibitors of NOS may also be useful in treating acute respiratorydistress syndrome (ARDS) and myocarditis, and they may be useful asadjuvants to short term immunosuppression in transplant therapy.

The diversity and ubiquity of NO function in physiology make thespecific therapeutic targeting of NO-related phenomena an importantconsideration. Since endogenous NO production is the result of theactions of related but distinct isozymes, the differential inhibition ofNOS isozymes allows more selective therapy with fewer side effects.

SUMMARY OF THE INVENTION

The compounds of the invention are inhibitors of iNOS and are thereforeuseful in conditions associated with the excessive production of iNOS.Accordingly, in one aspect, the invention is directed to compoundsselected from the group consisting of the following formulae:

wherein:

-   -   each n is 0 to 2;    -   each m is 0 to 4;    -   each p is 0 to 2;    -   A¹ is —O—(CH₂)_(q)— (where q is 0 to 3), —(CH2)_(q)—O— (where q        is 0 to 3), —N(R⁶)—(CH₂)_(q)— (where q is 0 to 3) or        —(CH₂)_(q)—N(R⁶)— (where q is 0 to 3);    -   A² is —(CH₂)_(q)—O— (where q is 2 to 3);    -   R¹ is hydrogen, alkyl, —C(O)N(R⁶)R⁷, or —C(O)R⁷;    -   or R¹ is aralkyl (where the aryl radical is optionally        substituted by one or more substituents selected from the group        consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,        aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   or R¹ is heterocyclylalkyl (where the heterocyclyl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   each R² is independently halo, haloalkyl, alkyl, nitro, —OR⁶,        —C(O)OR⁶, —C(O)N(R⁶)R⁷, —N(R⁶)R⁷, —N(R⁶)C(O)R⁷, or —N(H)S(O)₂R⁸;    -   each R³ is independently hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, or dialkylaminocarbonyl;    -   R⁵ is hydrogen, alkyl, aralkyl, —(CH₂)_(m)—C(O)—OR⁹ (where m is        1 to 4), —(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or        heterocyclylalkyl (where the heterocyclyl radical is optionally        substituted by one or more substituents selected from the group        consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,        aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   each R⁶ and R⁷ is independently hydrogen, alkyl, aryl        (optionally substituted by one or more substituents selected        from the group consisting of halo, alkyl, aryl, aralkyl,        hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl        (wherein the aryl is optionally substituted by one or more        substituents selected from the group consisting of halo, alkyl,        aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl), heterocyclyl        (optionally substituted by one or more substituents selected        from the group consisting of halo, alkyl, aryl, aralkyl,        hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl), or        heterocyclylalkyl (wherein the heterocyclyl radical is        optionally substituted by one or more substituents selected from        the group consisting of halo, alkyl, aryl, aralkyl, hydroxy,        alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl); and    -   each R⁸ is alkyl, aryl (optionally substituted by one or more        substituents selected from the group consisting of halo, alkyl,        aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl), or aralkyl        (wherein the aryl is optionally substituted by one or more        substituents selected from the group consisting of halo, alkyl,        aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   each R⁹ is independently hydrogen, alkyl or aralkyl (where the        aryl radical is optionally substituted by one or more        substituents selected from the group consisting of alkyl, halo,        haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,        dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,        aminocarbonyl, monoalkylaminocarbonyl, and        dialkylaminocarbonyl); and    -   R¹⁰ is hydrogen, alkyl, or aralkyl (where the aryl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹⁰ is heterocyclylalkyl (where the heterocyclyl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);        as a single stereoisomer, a mixture of stereoisomers, or as a        racemic mixture of stereoisomers; or a pharmaceutically        acceptable salt thereof.

In another aspect, the invention is directed to pharmaceuticalcompositions useful in treating a condition in a mammal resulting froman abnormality in nitric oxide production, which compositions comprise acompound of the invention as described above and a pharmaceuticallyacceptable excipient.

In another aspect, the invention is directed to methods of treating acondition resulting from an abnormality in nitric oxide production whichmethods comprise administering to a mammal having a condition resultingfrom an abnormality in nitric oxide production a therapeuticallyeffective amount of a compound of the invention as described above.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to six carbon atoms, and which is attachedto the rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like. Unless stated otherwisespecifically in the specification, it is understood that for radicals,as defined below, that contain a substituted alkyl radical or that areattached to an alkyl radical, that the substitution or attachment canoccur on any carbon of the alkyl radical.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy,1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy(t-butoxy), and the like.

“Alkoxycarbonyl” refers to a radical of the formula —C(O)OR_(a) whereR_(a) is an alkyl radical as defined above, e.g., methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl(iso-propoxycarbonyl), n-butoxycarbonyl, n-pentoxycarbonyl,1,1-dimethylethoxycarbonyl (t-butoxycarbonyl), and the like.

“Amino” refers to the radical —NH₂.

“Aryl” refers to a phenyl or naphthyl radical. Unless stated otherwisespecifically in the specification, the aryl radical may be optionallysubstituted by alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above, substituted by R_(b), an arylradical, as defined above, e.g., benzyl. The aryl radical may beoptionally substituted as described above.

“Aralkoxy” refers to a radical of the formula —OR_(c) where R_(c) is anaralkyl radical as defined above, e.g., benzyloxy, and the like. Unlessstated otherwise specifically in the specification, the aryl radical inthe aralkyl radical may be optionally substituted as described above.

“Aminocarbonyl” refers to the radical —C(O)NH₂.

“1,3-benzodioxol-5-yl” refers to the following radical:

“(1,3-benzodioxol-5-yl)alkyl” refers to a radical of the formula—R_(a)—R_(c) where R_(a) is an alkyl radical as defined above and R_(c)is a 1,3-benzodioxol-5-yl radical as defined above, e.g.,1-(1,3-benzodioxol-5-yl)methyl, 2-(1,3-benzodioxol-5-yl)ethyl,3-(1,3-benzodioxol-5-yl)propyl, and the like.

“(1,3-benzodioxol-5-yl)carbonyl” refers to the radical of the formula—C(O)—R_(c) where R_(c) is a 1,3-benzodioxol-5-yl radical as definedabove.

“Carboxy” refers to the radical —C(O)OH.

“Dialkylamino” refers to a radical of the formula —N(R_(a))R_(a) whereeach R_(a) is independently an alkyl radical as defined above, e.g.,dimethylamino, methylethylamino, diethylamino, dipropylamino,ethylpropylamino, and the like.

“Dialkylaminocarbonyl” refers to a radical of the formula—C(O)N(R_(a))R_(a) where each R_(a) is independently an alkyl radical asdefined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl,diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl,and the like.

“Halo” refers to bromo, chloro, iodo or fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Heterocyclyl” refers to a stable 3- to 15-membered ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. For purposes ofthis invention, the heterocyclyl radical may be a monocycdic, bicyclicor tricyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be aromatic or partiallyor fully saturated. The heterocyclyl radical may not be attached to therest of the molecule at any heteroatom atom. Examples of suchheterocyclyl radicals include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl,benzodioxolanyl, benzodioxanyl, carbazolyl, cinnolinyl,decahydroisoquinolyl, dioxolanyl, furanyl, furanonyl, isothiazolyl,imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl,isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolyl,oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolidinyl,thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, triazinyl,tetrahydropyranyl, thienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,and thiamorpholinyl sulfone. Unless stated otherwise specifically in thespecification, the heteroalkyl radical may be optionally substituted byalkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)—R_(d)where R_(a) is an alkyl radical as defined above and R_(d) is aheterocyclyl radical as defined above. The heterocyclyl radical may beoptionally substituted as defined above.

“N-heterocyclylalkyl” refers to a heterocyclylalkyl radical as definedabove wherein at least one of the heteroatoms is a nitrogen. Theheterocyclyl radical of the N-heterocyclylalkyl radical may beoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl.

“Mammal” includes humans and domesticated animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like.

“Monoalkylamino” refers to a radical of the formula —N(H)R_(a) whereR_(a) is an alkyl radical as defined above, e.g., methylamino,ethylamino, propylamino, and the like.

“Monoalkylaminocarbonyl” refers to a radical of the formula—C(O)N(H)R_(a) where R_(a) is an alkyl radical as defined above, e.g.,methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and thelike.

“Nitro” refers to —NO₂.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic add, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

As used herein, compounds which are “commercially available” may beobtained from standard commercial sources including Acros Organics(Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), AvocadoResearch (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester Pa.), Crescent ChemicalCo. (Hauppauge N.Y.), Eastman Organic Chemicals, Eastman Kodak Company(Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), FisonsChemicals (Leicestershire UK), Frontier Scientific (Logan Utah), ICNBiomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co. Ltd.(Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz & Bauer, Inc.(Waterbury Conn.), Polyorganix (Houston Tex.), Pierce Chemical Co.(Rockford Ill.), Riedel de Haen AG (Hannover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCl America (Portland Oreg.), TransWorld Chemicals, Inc. (Rockville Md.), and Wako Chemicals USA, Inc.(Richmond Va.).

As used herein, “suitable conditions” for carrying out a synthetic stepare explicitly provided herein or may be discerned by reference topublications directed to methods used in synthetic organic chemistry.The reference books and treatise set forth above that detail thesynthesis of reactants useful in the preparation of compounds of thepresent invention, will also provide suitable conditions for carryingout a synthetic step according to the present invention.

As used herein, “methods known to one of ordinary skill in the art” maybe identified though various reference books and databases. Suitablereference books and treatise that detail the synthesis of reactantsuseful in the preparation of compounds of the present invention, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-lnterscience, New York, 1992. Specificand analogous reactants may also be identified through the indices ofknown chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Wash., D.C., www.acs.org may be contacted for moredetails). Chemicals that are known but not commercially available incatalogs may be prepared by custom chemical synthesis houses, where manyof the standard chemical supply houses (e.g., those listed above)provide custom synthesis services.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal in need thereof,preferably a human, is sufficient to effect treatment, as defined below,for a condition resulting from an abnormality in nitric oxideproduction. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the condition and its severity, and the age of the mammal,preferably a human, to be treated, but can be determined routinely byone of ordinary skill in the art having regard to his own knowledge andto this disclosure.

“Treating” or “treatment” as used herein covers the treatment of acondition in a mammal, preferably a human, which condition ischaracterized by an abnormality in nitric oxide production, andincludes:

(i) preventing the condition from occurring in a mammal, in particular,when such mammal is predisposed to the condition but has not yet beendiagnosed as having it;

(ii) inhibiting the condition, i.e., arresting its development; or

(iii) relieving the condition, i.e., causing regression of thecondition.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as, their racemic and optically pureforms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

The nomenclature used herein is a modified form of the I.U.P.A.C.nomenclature system wherein the compounds of the invention are namedherein as derivatives of the central N-heterocyclic moiety. For example,the following compound of formula (I) wherein n is 1, m is 0, p is 0, A¹is —O—, R¹ is 1,3-benzodioxol-5-ylmethyl, and R³ is hydrogen, i.e.,

is named herein as3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine.As noted above in the formula by the asterisk, the compound contains achiral carbon at the 3-position of the piperidine. Unless otherwiseindicated, compound names herein are intended to include any singlestereoisomer, enantiomer, diastereomer, racemate or mixture ofstereoisomers.

The use of parentheses in a formula herein is used to conserve space.Accordingly, the use of parenthesis in a formula indicates that thegroup enclosed within the parentheses is attached directly to the atompreceding the parenthesis. For example, the term —C(O)N(R⁷)R⁸ can bedrawn as follows:

UTILITY OF THE COMPOUNDS OF THE INVENTION

Nitric oxide generated by the inducible form of nitric oxide synthase(iNOS) has been implicated in the pathogenesis of numerous inflammatoryand autoimmune diseases and also in diseases which are generally notregarded as inflammatory, but nevertheless may involve cytokines whichlocally up-regulate i-NOS. The compounds of the invention, alone or incombination with other pharmaceutical agents, are therefore useful intreating mammals, preferably humans, having a condition resulting froman abnormality in nitric oxide production. Such conditions include, butare not limited to, the following:

Multiple sclerosis (Parkinson, J. F. et al., J. Mol. Med. (1997), Vol.75, pp. 174-186); stroke or cerebral ischemia (Iadecola, C. et al., J.Neurosci. (1997), Vol. 17, pp. 9157-9164); Alzheimer's disease (Smith,M. A. et al., J. Neurosci. (1997), Vol. 17, pp. 2653-2657; Wallace, M.N. et al., Exp. Neurol. (1997), Vol. 144, pp. 266-272); HIV dementia(Adamson D. C. et al., Science (1996), Vol. 274, pp. 1917-1921);Parkinson's disease (Hunot, S. et al., Neuroscience (1996), Vol. 72, pp.355-363); meningitis (Koedel, U. et al., Ann. Neurol. (1995), Vol. 37,pp. 313-323); dilated cardiomyopathy and congestive heart failure (SatohM et al., J. Am. Coll. Cardiol. (1997), Vol. 29, pp. 716-724);atherosclerosis (Wilcox, J. N. et al., Arterioscler. Thromb. Vasc. Biol.(1997), Vol. 17, pp. 2479-2488); restenosis or graft stenosis, septicshock and hypotension (Petros, A. et al., Cardiovasc. Res. (1994), Vol.28, pp. 34-39); hemorrhagic shock (Thiemermann, C. et al., Proc. Natl.Acad. Sci. (1993), Vol. 90, pp. 267-271); asthma (Barnes, P. J., Ann.Med. (1995), Vol. 27, pp. 389-393; Flak, T. A. et al., Am. J. Respir.Crit. Care Med. (1996), Vol. 154, pp. S202-S206); acute respiratorydistress syndrome, smoke or particulate-mediated lung injury(Ischiropoulos, H. et al., Am. J. Respir. Crit. Care Med. (1994), Vol.150, pp. 337-341; Van Dyke, K., Agents Actions (1994), Vol. 41, pp.44-49); pathogen-mediated pneumonias (Adler, H. et al., J. Exp. Med.(1997), Vol. 185, pp. 1533-1540); trauma of various etiologies (Thomae,K. R. et al., Surgery (1996), Vol. 119, pp. 61-66); rheumatoid arthritisand osteoarthritis (Grabowski, P. S. et al., Br. J. Rheumatol. (1997),Vol. 36, pp. 651-655); glomerulonephritis (Weinberg, J. B. et al., J.Exp. Med. (1994), Vol. 179, pp. 651-660); systemic lupus erythematosus(Belmont, H. M. et al., Arthritis Rheum. (1997), Vol. 40, pp.1810-1816); inflammatory bowel diseases such as ulcerative colitis andCrohn's disease (Godkin, A. J. et al., Eur. J. Clin. Invest. (1996),Vol. 26, pp. 867-872; Singer, I. I. et al., Gastroenterology (1996),Vol. 111, pp. 871-885); insulin dependent diabetes mellitus (McDaniel,M. L., et al., Proc. Soc. Exp. Biol. Med. (1996), Vol. 211, pp. 24-32);diabetic neuropathy or nephropathy (Sugimoto, K. and Yagihashi, S.,Microvasc. Res. (1997), Vol. 53, pp. 105-112; Amore, A. et al., KidneyInt. (1997), Vol. 51, pp. 27-35); acute and chronic organ transplantrejection (Worrall, N. K. et al., Transplantation (1997), Vol. 63, pp.1095-1101); transplant vasculopathies (Russell, M. E. et al., (1995),Vol. 92, pp. 457-464); graft-versus-host disease (Kichian, K. et al., J.Immunol. (1996), Vol. 157, pp. 2851-2856); psoriasis and otherinflammatory'skin diseases (Bruch-Gerharz, D. et al., J. Exp. Med.(1996), Vol. 184, pp. 2007-2012); and cancer (Thomsen, L. L. et al.,Cancer Res. (1997), Vol. 57, pp. 3300-3304).

The compounds of the current invention may also be useful for themanagement of male and female reproductive functions when used alone orcombined with other drugs commonly used for these indications. Examples,without implied limitation, include: inhibition of fertilization,endometrial receptivity and implantation (alone or in combination with aprogesterone antagonist); post-coital contraception (alone or incombination with a progesterone antagonist); induction of abortion (incombination with an antiprogestin and in further combination with aprostaglandin); control and management of labor and delivery; treatmentof cervical incompetence (alone or in combination with progesterone or aprogestin); treatment of endometriosis (alone or in combination withother drugs, including LHRH-agonists/antagonists, antiprogestins orprogestins by either sequential application or by concomitantadministration). See, for example, the following references: Chwalisz,K. et al., J. Soc. Gynecol. Invest. (1997), Vol. 4, No. 1 (Supplement),page 104a, which discusses the inhibition of fertilization, endometrialreceptivity and implantation, or post-coital contraception, alone or incombination with a progesterone antagonist; Chwalisz, K. et al., Prenat.Neonat. Med. (1996), Vol. 1, pp. 292-329, which discusses the inductionof abortion, in combination with an antiprogestin and in furthercombination with a prostaglandin, and the control and management oflabor and delivery; and Chwalisz, K. et al., Hum. Reprod. (1997), vol.12, pp. 101-109, which discusses the treatment of cervical incompetence,alone or in combination with progesterone or a progestin.

Those skilled in the art will also recognize that the compounds of thepresent invention include 1-substituted imidazoles. This class ofcompounds has previously been described as mechanism-based, heme-bindinginhibitors of the cytochrome P450 family of enzymes (Maurice, M. et al.,FASEB J. (1992), Vol. 6, pp. 752-8) in addition to nitric oxidesynthesis (Chabin, R. N M. et al., Biochemistry (1996), Vol. 35, pp.9567-9575). The compounds of the present invention may thus be useful asinhibitors of selected cytochrome P450 family members of therapeuticinterest including, but not limited to, P450 enzymes involved in steroidand retinoid biosynthesis (Masamura et al., Breast Cancer Res. Treat.(1995), Vol. 33, pp. 19-26; Swart, P. et al., J. Clin. Endocrinol.Metab., Vol. 77, pp. 98-102; Docks, P. et al., Br. J. Dermatol. (1995),Vol. 133, pp. 426-32) and cholesterol biosynthesis (Burton, P. M. etal., Biochem. Pharmacol. (1995), Vol. 50, pp. 529-544; and Swinney, D.C. et al., Biochemistry (1994), Vol. 33, pp. 4702-4713). Imidazole-basedcompounds may also have antifungal activity (Aoyama, Y. et al., Biochem.Pharmacol. (1992), Vol. 44, pp. 1701-1705).

TESTING OF THE COMPOUNDS OF THE INVENTION

Nitric oxide synthases are complex enzymes that catalyze the conversionof L-arginine to nitric oxide (NO) and citrulline. Catalysis proceedsthrough two successive oxidations of the guanidinium group ofL-arginine.

A cell-based nitric oxide synthase assay employing the measurement ofnitric oxide oxidation product, nitrite, in the conditioned medium ofcultured cells was employed for the evaluation of the compounds of theinvention in vitro. The murine monocytic cell lines RAW 264.7 and J774are well documented as capable of producing >10:M nitrite in response toimmunostimulation. This in vitro assay is described in detailed below inthe Examples.

Various in vivo assays may be employed to determine the efficacy of thecompounds of the invention in treating a condition resulting from anabnormality in nitric oxide production, such as arthritis. Such an assayis described in detail below in the Examples.

Those skilled in the art will also recognize that numerous assays forthe activity of the NOS isoforms (iNOS, nNOS and eNOS) exist which canbe used to evaluate the biological activity of the compounds of thecurrent invention. These include assays for native NOS isoforms intissues studied ex vivo (Mitchell et al., Br. J. Pharmacol. (1991), Vol.104, pp. 289-291; Szabo et al., Br. J. Pharmacol. (1993), Vol. 108, pp.786-792; Joly et al., Br. J. Pharmacol. (1995), Vol. 115, pp. 491-497)as well as primary cell cultures and cell lines (Forstermann et al.,Eur. J. Pharmacol. (1992), Vol. 225, pp. 161-165; Radmoski et al.,Cardiovasc. Res. (1993), Vol. 27, pp. 1380-1382; Wang et al., J.Pharmacol. Exp. Ther. (1994), Vol. 268, pp. 552-557). Those skilled inthe art will also recognize that recombinant NOS enzymes can beexpressed in heterologous cells by either transient transfection(Karlsen et al., Diabetes, (1995), Vol. 44, pp. 753-758), stabletransfection (McMillan et al., Proc. Natl. Acad. Sci. (1992), Vol. 89,pp. 11141-11145; Sessa et al., J. Biol. Chem. (1995), Vol. 270, pp.17641-17644) or via the use of lytic virus transfection (Busconi &Michel, Mol. Pharmacol. (1995), Vol. 47, pp. 655-659; List et al.,Biochem. J. (1996), Vol. 315, pp. 57-63) using NOS cDNAs. Heterologousexpression can be achieved in mammalian cells (McMillan et al., Proc.Natl. Acad. Sci. (1992), Vol. 89, pp. 11141-11145), insect cells(Busconi & Michel, Mol. Pharmacol. (1995), Vol. 47, pp. 655-659; List etal, Biochem. J. (1996), Vol. 315, pp. 57-63), yeast (Sari et al.,Biochemistry (1996), Vol. 35, pp. 7204-7213) or bacteria (Roman et al.,Proc. Natl. Acad. Sci. (1995), Vol. 92, pp. 8428-8432; Martasek et al.,Biochem. Biophys. Res. Commun. (1996), Vol. 219, pp. 359-365). Any ofthese heterologous expression systems can be used to establish iNOS,nNOS and eNOS assay systems to evaluate the biological activity of thecompounds of the present invention.

The P450 inhibitory activity of the compounds of the present inventioncan be assessed using appropriate assay systems specific for the P450isoform of interest. Such assays are included in the references cited inthe discussion of P450 family of enzymes in Paragraph B above. Oneadditional example of mammalian cytochrome P450 isoform that may beinhibited by the compounds of the present invention is cytochrome P4503A4 which can be assayed in a manner similar to the method described inYamazaki et al., Carcinogenesis (1995), Vol. 16, pp. 2167-2170.

ADMINISTRATION OF THE COMPOUNDS OF THE INVENTION

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the present invention may be in any formthat allows for the composition to be administered to a patient. Typicalroutes of administration include, without limitation, oral, topical,transdermal, inhalation, parenteral, sublingual, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a patient take the form of oneor more dosage units, where for example, a tablet may be a single dosageunit, and a container of a compound of the invention in aerosol form mayhold a plurality of dosage units. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, 18th Ed.,(Mack Publishing Company, Easton, Pa., 1990). The composition to beadministered will, in any event, contain a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt thereof, for treatment of a disease-state characterized byinflammation in accordance with the teachings of this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, e.g.,inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, e.g., agelatin capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil.

The pharmaceutical composition may be in the form of a liquid, e.g., anelixir, syrup, solution, emulsion or suspension. The liquid may be fororal administration or for delivery by injection, as two examples. Whenintended for oral administration, preferred composition contain, inaddition to the present compounds, one or more of a sweetening agent,preservatives, dye/colorant and flavor enhancer. In a compositionintended to be administered by injection, one or more of a surfactant,preservative, wetting agent, dispersing agent, suspending agent, buffer,stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 50% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 1% by weight of the compound of the invention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, e.g., of a suppository, which willmelt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits which can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

Whether in solid, liquid or gaseous form, the pharmaceutical compositionof the present invention may contain one or more known pharmacologicalagents used in the treatment of inflammation.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with water so as toform a solution. A surfactant may be added to facilitate the formationof a homogeneous solution or suspension. Surfactants are compounds thatnon-covalently interact with the compound of the invention so as tofacilitate dissolution or homogeneous suspension of the compound in theaqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particulardisease-state; and the host undergoing therapy. Generally, atherapeutically effective daily dose is from about 0.14 mg to about 14.3mg/kg of body weight per day of a compound of the invention, or apharmaceutically acceptable salt thereof; preferably, from about 0.7 mgto about 10 mg/kg of body weight per day; and most preferably, fromabout 1.4 mg to about 7.2 mg/kg of body weight per day. For example, foradministration to a 70 kg person, the dosage range would be from about10 mg to about 1.0 gram per day of a compound of the invention, or apharmaceutically acceptable salt thereof, preferably from about 50 mg toabout 700 mg per day, and most preferably from about 100 mg to about 500mg per day.

Preferred Embodiments

Of the compounds of the invention as described above in the Summary ofthe Invention, certain groups of compounds are particularly preferred.

Accordingly, one preferred group is that group of compounds wherein thecompound is selected from formula (I):

Of this preferred group of compounds, a preferred subgroup is thatsubgroup of compounds wherein:

-   -   n, m and p are each independently 0 to 2;    -   A¹ is —O—(CH₂)_(q)— (where q is 0 to 1), —(CH₂)_(q)—O— (where q        is 0 to 1), —N(R⁶)—(CH₂)_(q)— (where q is 0 to 1) or        —(CH₂)_(q)—N(R⁶)— (where q is 0 to 1);    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   or R¹ is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   R² is halo, haloalkyl, alkyl, nitro, —OR⁶, —C(O)OR⁶,        —C(O)N(R⁶)R⁷, or —N(R⁶)R⁷;    -   each R³ is independently hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   each R⁶ and R⁷ is independently hydrogen or alkyl.

Of this preferred subgroup of compounds, a preferred class is that classof compounds wherein:

-   -   n, m and p are each independently 0 to 2;    -   A¹ is —O—, —CH₂—O—, or —N(R⁶)—;    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, hydroxy, and alkoxy);    -   or R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   or R¹ is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   each R³ is independently hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred class of compounds, a preferred subclass is thatsubclass of compounds wherein:

-   -   n is 0 to 2;    -   m is 0 to 1;    -   p is 0 to 2;    -   A¹ is —O—, —CH₂— or —N(R⁶)—;    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, hydroxy, and alkoxy);    -   or R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   or R¹ is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   each R³ is hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred subclass of compounds, a preferred set is that set ofcompounds wherein:

-   -   n is 0;    -   m is 0 to 1;    -   p is 0 to 2;    -   A¹ is —O—;    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, hydroxy, and alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   R³ is hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Another preferred set of compounds of this subclass of compounds is thatset of compounds wherein:

-   -   n is 0;    -   m is 0 to 1;    -   p is 0 to 2;    -   A¹ is —O— or —CH₂O—;    -   R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   R³ is hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following compounds:

-   -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;    -   (3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;    -   (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;    -   2-methoxycarbonyl4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;    -   2-carboxy-4-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine;        and    -   2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine.

Another preferred set of compounds of this subclass of compounds is thatset of compounds wherein:

-   -   n is 0;    -   m is 0 to 1;    -   p is0 to 2;    -   A¹ is —O—;    -   R¹ is (1,3-benzodioxol-5-yl)carbonyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   R³ is hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred set of compounds, a preferred compounds is3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)carbonyl]pyrrolidine.

Another preferred set of compounds of this subclass of compounds is thatset of compounds wherein:

-   -   n is 1 or2;    -   m is 0 to 1;    -   p is 0 to 2;    -   A¹ is —O—, —CH₂—O— or —N(H)—;    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, hydroxy, and alkoxy);    -   or R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   R³ is hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred set of compounds, a preferred subset is that subset ofcompounds wherein:

-   -   A¹ is —O—, —CH₂O— or —N(H)—; and    -   R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy).

Of this preferred subset of compounds, preferred compounds are selectedfrom the group consisting of the following compounds:

-   -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;    -   (3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;    -   (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;    -   2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;    -   3-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;    -   3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;        and    -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]hexahydro-1H-azepine.

Another preferred subset of compounds of this set of compounds is thatsubset of compounds wherein:

-   -   A¹ is —O—; and    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, hydroxy, and alkoxy).

Of this preferred subset of compounds, preferred compounds are selectedfrom the group consisting of the following compounds:

-   -   3-[4-(imidazol-1-yl)phenoxy]-1-(3,4-dimethoxybenzyl)piperidine;        and    -   3-[4-(imidazol-1-yl)phenoxy]-1-(4-methoxynaphth-1-yl)methylpiperidine.

Another preferred group of compounds of the invention as set forth abovein the Summary of the Invention is that group of compounds selected fromformula (II):

Of this preferred group of compounds, a preferred subgroup is thatsubgroup of compounds wherein:

-   -   n and p are each independently 0 to 2;    -   A¹ is —O—(CH₂)_(q)— (where q is 0 to 1), —(CH₂)_(q)—O— (where q        is 0 to 1), —N(R⁶)—(CH₂)_(q)— (where q is 0 to 1) or        —(CH₂)_(q)—N(R⁶)— (where q is 0 to 1);    -   R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   R² is halo, haloalkyl, alkyl, nitro, —OR⁶, —C(O)OR⁶,        —C(O)N(R⁶)R⁷, or —N(R⁶)R⁷;    -   each R³ is independently hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   each R⁶ and R⁷ is independently hydrogen or alkyl.

Of this preferred subgroup of compounds, a preferred class is that classof compounds wherein:

-   -   n and p are each independently 0 to 2;    -   A¹ is —O—, —CH₂—O—, or —N(R⁶)—;    -   R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   each R³ is independently hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred class of compounds, a preferred subclass is thatsubclass of compounds wherein:

-   -   n is 0 to 2;    -   p is 0 to 2;    -   A¹ is —O— or —CH₂—;    -   R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, hydroxy, and        alkoxy);    -   R² is halo, haloalkyl, alkyl, or —OR⁶;    -   R³ is hydrogen or alkyl;    -   each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,        alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,        alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or        dialkylaminocarbonyl; and    -   R⁶ is hydrogen or alkyl.

Of this preferred subclass of compounds, preferred compounds areselected from the group consisting of the following compounds:

-   -   3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;        and    -   2-[((6-(imidazol-1-yl)pyridazin-3-yl)oxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidin.

Another preferred group of compounds of the invention as set forth abovein the Summary of the Invention is that group of compounds selected fromformula (III):

Of this preferred group of compounds, a preferred subgroup is thatsubgroup of compounds wherein:

-   -   m is 0 to 4;    -   A² is —(CH₂)_(q)—O— (where q is 2 to 3);    -   R¹ is aralkyl (where the aryl radical is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   each R² is independently halo, haloalkyl, alkyl, —OR⁶, —C(O)OR⁶,        —C(O)N(R⁶)R⁷, —N(R⁶)R⁷, or —N(R⁶)C(O)R⁷;    -   R³ is independently hydrogen or alkyl;    -   R⁵ is hydrogen, alkyl, aralkyl, —(CH₂)_(m)—C(O)—OR⁹ (where m is        1 to 4), —(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or        (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   each R⁶ and R⁷ is independently hydrogen or alkyl;    -   each R⁹ is independently hydrogen or alkyl; and    -   R¹⁰ is hydrogen, alkyl, aralkyl (where the aryl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹⁰ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹⁰ is N-heterocyclylalkyl (where the heterocyclyl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl).

Of this subgroup of compounds, a preferred class is that class ofcompounds wherein:

-   -   m is 0;    -   A² is —CH₂—CH₂—O—;    -   R¹ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro,        carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,        and dialkylaminocarbonyl);    -   R³ is hydrogen;    -   R⁵ is hydrogen, —(CH₂)_(m)—C(O)—OR⁹ (where m is 1 to 4),        —(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or        (1,3-benzodioxol-5-yl)alkyl;    -   each R⁹ is independently hydrogen or alkyl; and    -   R¹⁰ is hydrogen, alkyl, aralkyl (where the aryl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,        nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹⁰ is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl        radical is optionally substituted by one or more substituents        selected from the group consisting of alkyl, halo, haloalkyl,        hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl);    -   or R¹⁰ is N-heterocyclylalkyl (where the heterocyclyl radical is        optionally substituted by by one or more substituents selected        from the group consisting of alkyl, halo, haloalkyl, hydroxy,        alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl).

Of this preferred class of compounds, a preferred subclass is thatsubclass of compounds wherein:

-   -   R¹ is (1,3-benzodioxol-5-yl)methyl;    -   R⁵ is hydrogen, —CH₂—C(O)—OR⁹, —CH₂—C(O)—N(R⁹)R¹⁰, or        (1,3-benzodioxol-5-yl)methyl;    -   each R⁹ is independently hydrogen or alkyl; and    -   R¹⁰ is hydrogen, alkyl, aralkyl (where the aryl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl,        aminocarbonyl, monoalkylaminocarbonyl, and        dialkylaminocarbonyl);    -   or R¹⁰ is (1,3-benzodioxol-5-yl)methyl; and    -   or R¹⁰ is piperidin-1-ylalkyl (wherein the piperidinyl radical        is optionally substituted by one or more substituents selected        from the group consisting of alkyl, halo, haloalkyl, hydroxy,        alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl).

Of this preferred subclass of compounds, a preferred set is that set ofcompounds wherein:

-   -   R⁵ is hydrogen or —CH₂—C(O)—OR⁹; and    -   R⁹ is hydrogen or alkyl.

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following compounds:

-   -   N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-(carboxymethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;        and    -   N-(ethoxycarbonylmethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine.

Another preferred set of compound of this preferred subclass ofcompounds is that set of compounds wherein R⁵ is(1,3-benzodioxol-5-yl)methyl, namely,

-   -   N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N,N-di[(1,3-benzodioxol-5-yl)methyl]amine.

Another preferred set of compounds of this preferred subclass ofcompounds is that set of compounds wherein:

-   -   R⁵ is —CH₂—C(O)—N(R⁹)R¹⁰;    -   R⁹ is independently hydrogen or alkyl; and    -   R¹⁰ is hydrogen, alkyl, aralkyl (where the aryl radical is        optionally substituted by one or more substituents selected from        the group consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy,        amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl,        aminocarbonyl, monoalkylaminocarbonyl, and        dialkylaminocarbonyl);    -   or R¹⁰ is (1,3-benzodioxol-5-yl)methyl; and    -   or R¹⁰ is piperidin-1-ylalkyl (wherein the piperidinyl radical        is optionally substituted by one or more substituents selected        from the group consisting of alkyl, halo, haloalkyl, hydroxy,        alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino,        monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,        monoalkylaminocarbonyl, and dialkylaminocarbonyl).

Of this preferred set of compounds, preferred compounds are selectedfrom the group consisting of the following compounds:

-   -   N-[(((3-(2-methylpiperidin-1-yl)propyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-[((((1,3-benzodioxol-5-yl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-[((((4-trifluoromethylphenyl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;        and    -   N-[(((butyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-(1,3-benzodioxol-5-yl)methyl]amine.

PREPARATION OF THE COMPOUNDS OF THE INVENTION

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, amino, mercapto and carboxylic acid.Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for amino, amidino and guanidino includet-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protectinggroups for mercapto include —C(O)—R⁸ (where R⁸ is alkyl, alkenyl, aryl,aralkyl or aralkenyl), p-methoxybenzyl, trityl and the like. Suitableprotecting groups for carboxylic acid include alkyl, aryl or aralkylesters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed.,Wiley-lnterscience. The protecting group may also be a polymer resinsuch as a Wang resin or a 2-chlorotrityl chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of formulae (I), (II) and (III), asdescribed above in the Summary of the Invention, may not possesspharmacological activity as such, they may be administered to a mammalhaving a condition resulting from an abnormality in nitric oxideproduction and thereafter metabolized in the body to form compounds ofthe invention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds offormulae (I), (II) and (III) are included within the scope of theinvention.

A. Preparation of Compounds of Formula (Ia)

Compounds of formula (Ia) are compounds of formula (I) as defined abovein the Summary of the Invention and are prepared as illustrated below inReaction Scheme 1 wherein X¹ is halo or halo-(CH₂)_(q)— (where q isdefined as above in the Summary of the Invention); X² is halo; A¹ is—O—, —(CH₂)_(q)—O— (where q is defined as above in the Summary of theInvention and the oxygen is attached to the hydrogen) or—(CH₂)_(q)—N(R⁶)— (where q is defined as above in the Summary of theInvention and the nitrogen is attached to the hydrogen); R¹, R², R³ andR⁴ are as defined above in the Summary of the Invention; m, n and p areas described above in the Summary of the Invention and PG is anitrogen-protecting group, such as benzyl, benzyloxycarbonyl ort-butoxycarbonyl:

Compounds of formulae (A), (B) and (E) are commercially available, ormay be prepared according to methods known to one of ordinary skill inthe art.

In general, compounds of formula (la) are prepared by first treating acompound of formula (A) in an aprotic solvent, such as DMF, in thepresence of a strong base, preferably sodium hydride, at ambienttemperature, with a slightly excess molar amount of a compound offormula (B) in an aprotic solvent, such as DMF. The resulting mixture isstirred at temperatures of between about 0° C. and ambient temperature,preferably at ambient temperature, for a period of about 2 hours toabout 12 hours, preferably for about 2 hours. The compound of formula(C) is isolated from the reaction mixture by standard isolationtechniques, such as organic extraction and purification by silical gelchromatography.

The compound of formula (C) is then treated to standard reductionconditions, such as treatment with hydrogen in the presence of apalladium catalyst, to afford a compound of formula (D), which isisolated from the reaction mixture by standard isolation techniques,such as filtration and recrystallization in organic solvent.

The compound of formula (D) at a temperature of between about 0° C. andabout 100° C., preferably at about 0° C., in an aprotic solvent, such asDMF, in the presence of a base, such as potassium carbonate, and analkaline metal iodide, such as sodium iodide, and is then treated with acompound of formula (E). The resulting reaction mixture is stirred at atemperature of about 0° C. to about 100° C., preferably at ambienttemperature, for a period of about 2 hours to about 12 hours, preferablyfor about 2 hours. The compound of formula (F) is isolated from thereaction mixture by standard isolation techniques, such as organicextraction and purification by column chromatography.

The compound of formula (F) is then treated under standard Debusreaction conditions, such as treatment with ammonium hydroxide in aprotic solvent, such as methanol, and an aldehyde, such as formadehyde,and a dione, such as glyoxal, in a protic solvent, such as water, attemperatures of about 0° C. to about 100° C., preferably at about 65°C., for a period of about 2 hours to about 12 hours, preferably forabout 2 hours. The compound of formula (Ia) is isolated from thereaction mixture by standard isolation techniques, such as evaporationof solvents, organic extraction and purification by columnchromatography.

B. Preparation of Compounds of Formula (IIa)

Compounds of formula (IIa) are compounds of formula (II) as describedabove in the Summary of the Invention and are prepared as illustratedbelow in Reaction Scheme 2 wherein X¹ is halo or halo-(CH₂)_(q)— (whereq is defined as above in the Summary of the Invention); X² is halo; A¹is —O—, —(CH₂)_(q)—O— (where q is defined as above in the Summary of theInvention and the oxygen is attached to the hydrogen) or—(CH₂)_(q)—N(R⁶)— (where q is defined as above in the Summary of theInvention and the nitrogen is attached to the hydrogen); R¹, R², R³ andR⁴ are as defined above in the Summary of the Invention except that R⁴can not be hydroxy; m, n and p are as described above in the Summary ofthe Invention; and PG is nitrogen-protecting group:

Compounds of formulae (G), (H), (A) and (E) are commercially available,or may be prepared according to methods known to one skilled in the art.

In general, compounds of formula (IIa) are prepared by first treating amixture of a compound of formula (G) and an excess molar amount of acompound of formula (H) in an aprotic solvent, such as DMF, in thepresence of a base, such as potassium carbonate, at a temperature ofbetween about 0° C. and about 100° C., preferably at a temperature ofbetween about 70° C. and 80° C., for a period of about 4 hours to about18 hours, preferably for about 18 hours. The compound of formula (J) isisolated from the reaction mixture by standard isolation techniques,such as evaporation of solvent, organic extraction, and separation bycolumn chromatography.

The compound of formula (J) in an aprotic solvent, such as DMF, is thentreated with an equimolar amount of a compound of formula (A) in anaprotic solvent, such as DMF, in the presence of a strong base, such assodium hydride, at a temperature of between about 0° C. and 100° C.,preferably at ambient period, for a period of about 30 minutes to 2hours, preferably for about 1 hour. The compound of formula (K) is thenisolated from the reaction mixture by standard isolation techniques,such as evaporation of solvent, organic extraction and purification bycolumn chromatography.

The compound of formula (K) is then de-protected under standard nitrogendeprotection conditions, such as treatment with a strong acid or base inthe presence of a palladium catalyst, to form a compound of formula (L),which is isolated from the reaction mixture by standard isolationtechniques.

The compound of formula (L) in an aprotic solvent, such as DMF, is thentreated with an equivalent molar amount of a compound of formula (E) inthe presence of a base, such as potassium carbonate, at a temperature ofbetween about 0° C. and about 100° C., preferably at a temperature ofabout 50° C., for a period of about 2 hours to about 4 hours, preferablyfor about 3 hours. The compound of formula (IIa) is isolated from thereaction mixture by standard isolation techniques, such as filtrationand concentration, organic extraction, and purification by columnchromatography.

C. Preparation of Compounds of Formula (Ib)

Compounds of formula (Ib) are compounds of formula (I) as describedabove in the Summary of the Invention and are prepared as illustratedbelow in Reaction Scheme 3 wherein X² is halo; A¹ is —O—, —(CH₂)_(q)—O—(where q is defined as above in the Summary of the Invention and theoxygen is attached to the hydrogen) or —(CH₂)_(q)—N(R⁶)— (where q isdefined as above in the Summary of the Invention and the nitrogen isattached to the hydrogen); R¹, R², R³ and R⁴ are as defined above in theSummary of the Invention except that R⁴ can not be hydroxy; m, n, p, andq are as described above in the Summary of the Invention; and PG isnitrogen-protecting group:

Compounds of formulae (A), (M) and (E) are commercially available, ormay be prepared according to methods known to one skilled in the art.

In general, compounds of formula (Ib) are prepared by first treating amixture of a compound of formula (A) and an excess molar amount of acompound of formula (M) in an aprotic solvent, such as DMF, to standardMitsunobu Reaction conditions (see, Mitsunobu, O. et al., Bull. Chem.Soc., Japan (1967), Vol. 40, p. 2380), i.e., treatment with diethylazodicarboxylate and triphenyl phosphine at ambient temperature. Thecompound of formula (N) is isolated from the reaction mixture bystandard isolation techniques, such as evaporation of the solvent,organic extraction and purification by flash column chromatography.

The compound of formula (N) is then deprotected under standard acidhydrolysis conditions, such as treatment with trifluoroacetic acid for at-butoxycarbonyl protected amine, to afford the compound of formula (O),which is isolated from the reaction mixture by standard isolationtechniques.

Compounds of formula (O) are then treated with a compound of formula (E)in a manner similar to that described above for compounds of formula(Ia) and (IIa) to prepared compounds of formula (Ib), which is isolatedfrom the reaction mixture by standard isolation techniques.

D. Preparation of Compounds of Formula (Ic)

Compounds of formula (Ic) are compounds of formula (I) as describedabove in the Summary of the Invention and are prepared as illustratedbelow in Reaction Scheme 3 wherein X² is halo; PG is a nitrogenprotecting group such as benzyl or t-butoxycarbonyl; m, n, p and q, andR¹, R², R³ and R⁶ are as defined above in the Summary of the Invention:

Compounds of formulae (P), (Q) and (E) are commercially available, ormay be prepared according to methods known to one skilled in the art, orby methods disclosed herein.

In general, compounds of formula (Ic) are prepared by first treating acompound of formula (P) to standard reductive amination conditions, suchas treating the compound of formula (P) with an equimolar amount of acompound of formula (Q) in the presence of an excess molar amount of adehydrating agent, such as Ti(OiPr)₄. The resulting mixture is stirredat ambient temperature for a period of between about 30 minutes andabout 2 hours, preferably for about 1.25 hours. The mixture is thendiluted with a protic solvent, such as ethanol, and treated with areducing reagent, such as sodium cyanoborohydride. The resulting mixtureis stirred at ambient temperature for a period of between about 8 hoursand about 24 hours, preferably for about 20 hours. The compound offormula (R) is isolated from the reaction mixture by standard isolationconditions, such as precipitation and flash column chromatography.

The compound of formula (R) is then deprotected by standard nitrogendeprotection techniques, such as hydrogenation in the presence of apalladium catalyst. The compound of formula (S) is isolated from thereaction mixture by standard isolation techniques, such as filtrationand evaporation of solvents.

The compound of formula (S) is then treated with a compound of formula(E) under conditions similar to those described above for the treatmentof compounds of formula (D) with compounds of formula (E) to form acompound of formula (Ic), which is isolated from the reaction mixture bystandard isolation techniques.

E. Preparation of Compounds of Formula (Id)

Compounds of formula (Id) are compounds of formula (I) as describedabove in the Summary of the Invention and are prepared as illustratedbelow in Reaction Scheme 3 wherein m, n, p, R², R³ and R⁴ are as definedabove in the Summary of the Invention; A¹ is as described above in theSummary of the Invention; and R^(1a) is aryl optionally substituted byone or more substituents selected from the group consisting of alkyl,halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl:

Compounds of formula (O) are prepared according to methods disclosedherein or by methods known to one of ordinary skill in the art.Compounds of formula (T) are commercially available or may be preparedaccording to methods known to one of ordinary skill in the art.

In general, compounds of formula (Id) are prepared by treating compoundsof formula (O) and formula (T) to standard reductive aminationconditions, such as treating a compound of formula (O) in a proticsolvent, such as methanol, with an excess molar amount of a compound offormula (T) in the presence of a reducing reagent, such as a boranepyridine complex. The resulting mixture is stirred at ambienttemperature for a period of between about 8 hours and about 24 hours,preferably for about 12 hours. The compound of formula (Id) is isolatedfrom the reaction mixture by standard isolation techniques, such asevaporation of solvents, organic extraction and purification by flashcolumn chromatography.

F. Preparation of Compounds of Formula (III)

Compounds of formula (III) are compounds of the invention as describedabove in the Summary of the Invention and are prepared as illustratedbelow in Reaction Scheme 6 wherein A² is —(CH₂)_(q)—O— (where q is 2 to3); X² is halo; and m, R¹, R², R³ and R⁶ are as defined above in theSummary of the Invention:

Compounds of formula (U) and formula (E) are commercially available, ormay be prepared according to methods known to one skilled in the art.

In general, compounds of formula (III) are prepared by first treating acompound of formula (U) to standard reductive amination conditions, suchas first treating the compound of formula (U) in a protic solvent, suchas methanol, with an equimolar amount of a compound of formula (E) inthe presence of an acid, such as acetic acid. The reaction mixture isstirred at ambient temperature for a period of between about 30 minutesand about 2 hours, preferably for about 1 hour. An excess molar amountof sodium cyanoborohydride is then added to the reaction mixture andresulting mixture is allowed to stir at ambient temperature for a periodof between about 12 hours and about 18 hours, preferably for about 18hours. The compound of formula (III) is then isolated from the reactionmixture by standard isolation techniques, such as evaporation ofsolvents and chromatography.

All compounds of the invention as prepared above which exist in freebase or acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic base oracid. Salts of the compounds prepared above may be converted to theirfree base or acid form by standard techniques. It is understood that allpolymorphs, amorphous forms, anhydrates, hydrates, solvates and salts ofthe compounds of the invention are intended to be within the scope ofthe invention.

In the following Preparations and Examples, the following abbreviationsand acronyms may be used: DEAD for diethyl azodicarboxylate; DIEA fordiisopropylethylamine; DMF for dimethylformamide; THF fortetrahydrofuran; TFA for trifluoroacetic acid; DMAP fordimethylaminopyridine; CH₃CN for acetonitrile; CH₂Cl₂ fordichloromethane (methylene choride); CHCl₃ for chloroform; DMSO fordimethyl sulfoxide; Et₂O for diethyl ether; EDC or EDCl for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; MeOH formethanol; BSA for bovine serum albumin; and HCl for hydrogen chloride.

The following specific Preparations (which are directed primarily tointermediates) and Examples (which are directed primarily to claimedcompounds, pharmaceutical compositions and methods of use) are providedas a guide to assist in the practice of the invention, and are notintended as a limitation on the scope of the invention.

PREPARATION 1 Compounds of Formula (C)

A. To a suspension of NaH (0.83 g, 37 mmol) in DMF (10 mL) was added1-benzyl-(3S)-3-hydroxypiperidine (4.1 g, 21.5 mmol), and the resultingreaction mixture was stirred at ambient temperature for 2 hours.4-Fluoronitrobenzene (2.5 mL, 23.6 mmol) in DMF (10 mL) was then addedto the mixture dropwise. The resulting reaction mixture was stirred atambient temperature for 2 hours. After removal of DMF in vacuo, thecrude mixture was dissolved in ethyl acetate (200 mL), washed with water(100 mL×3), brine (100 mL), to give a yellow oil. Purification usingsilical gel chromatography column afforded1-benzyl-(3S)-3-(4-nitrophenoxy)piperidine (6.5 g, 97% yield) as ayellow oil.

B. In a similar manner, other compounds of formula (C) were prepared.

PREPARATION 2 Compounds of Formula (D)

A. A mixture of 1-benzyl-(3S)-3-(4-nitrophenoxy)piperidine (6.5 g) and1.2 g of 10% Pd/C in methanol (30 mL) was subjected to hydrogenation (50psi). When the reaction was completed, the reaction mixture wasfiltered. The filtrate was concentrated in vacuo, giving a yellow solid.Recrystallization in CH₂Cl₂/hexane afforded(3S)-3-(4-aminophenoxy)piperidine (3.5 g, 88% yield) as a white solid.

B. In a similar manner, other compounds of formula (D) were prepared.

PREPARATION 3 Compounds of Formula (F)

A. To an ice water-cooled solution of (3S)-3-(4-aminophenoxy)piperidine(3.5 g) in DMF (20 mL) was added K₂CO₃ (7.5 g) and Nal (0.2 g), followedby the addition of 5-chloromethyl-1,3-benzodioxole (4.7 mL). Theresulting reaction mixture was stirred at ambient temperature for 2hours. The reaction mixture was diluted with ethyl acetate (200 mL),washed with water (100 mL×3) and brine (100 mL), and dried (Na₂SO₄). Thecrude product was further purified by column chromatography(methanol:ethyl acetate 1:10), to afford(3S)-3-(4-aminophenoxy)-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (4.4g, 74% yield) as an oil.

B. In a similar manner, other compounds of formula (F) were prepared.

PREPARATION 4 Compounds of Formula (J)

A. A mixture of imidazole (0.613 g, 8 mmol) and 3,6-dichloropyridazine(1.55 g, 10 mmol), K₂CO₃ (4.15 g) and DMF (15 mL) was heated at 70-80°C. overnight. After removal of DMF in vacuo, the residual solid wasdissolved in CH₂Cl₂ (50 mL), washed with 1N Na₂CO₃ aq. solution, anddried (MgSO₄). Separation using column chromatography (CH₂Cl₂/methanol100:1) afforded 3-chloro-6-(imidazol-1-yl)pyridazine (1.2 g) as a whitesolid.

B. In a similar manner, other compounds of formula (J) were prepared.

PREPARATION 5 Compounds of Formula (K)

A. To a suspension of NaH (0.21 g, 8.31 mmol) in DMF (5 mL) was added1-benzyl-3-hydroxypiperidine hydrochloride (0.78 g, 3.3 mmol) in DMF (5mL), and the resulting reaction mixture was stirred at ambienttemperature for 30 minutes. 3-chloro-6-(imidazol-1-yl)pyridazine (0.6 g,3.3 mmol) in DMF (5 mL) was then added dropwise. The reaction mixturewas stirred at ambient temperature for 30 minutes. After removal of DMFin vacuo, the black oil was dissolved in CH₂Cl₂ (50 mL), washed withwater and brine. Purification using column chromatography afforded3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-benzylpiperidine (400 mg) asa yellow oil.

B. In a similar manner, other compounds of formula (K) were prepared.

PREPARATION 6 Compounds of Formula (L)

A. To a solution of3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-benzylpiperidine (400 mg) inmethanol (20 mL) was added 10% Pd/C (0.4 g), and HCO₂NH₄ (0.6 g). Themixture was heated at reflux under N₂ for 1 hour. After cooling toambient temperature, Pd/C was filtered off. The filtrate wasconcentrated in vacuo, giving3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]piperidine (240 mg) as an oil,which was used in Example 3 without further purification.

B. In a similar manner, other compounds of formula (L) were prepared.

PREPARATION 8 Compounds of Formula (N) and Formula (O)

A. To a mixture of (3R)-1-t-butoxycarbonyl-3-hydroxypiperidine (4.10 g,17.8 mmol), 4-(imidazol-1-yl)phenol (4.4 g, 1.5 eq.), triphenylphosphine(1.5 eq., 7.10 g), DMF (80 mL) was added DEAD (1.5 eq., 4.33 mL). Theresulting reaction mixture were stirred at room temperature for twodays. The solvent was evaporated, the residue was diluted with ethylacetate, washed with 1N NaOH (45 mL×3), water and brine, and evaporatedin vacuo. Purification by flash column chromatography on silical gelwith gradient 1-3% methanol in CH₂Cl₂ gave(3R)-1-t-butoxycarbonyl-3-[4-(imidazol-1-yl)phenoxy]piperidine (420 mg,1.19 mmol), which was treated with trifluoroacetic acid/CH₂Cl₂ (1:1)from 0° C. to ambient temperature for 2 hours. The solvents wereevaporated. The residue was diluted with CH₂Cl₂, and washed with 1N HCl(10 mL). The aqueous phase was extracted with CH₂Cl₂ to removeby-product. The aqueous phase was re-adjusted to pH 9.5 to 10.0 with 1NNaOH. Extraction with CH₂Cl₂ (60 mL×3) and evaporation of the solvent invacuo gave (3R)-3-[4-(imidazol-1-yl)phenoxy]piperidine (62 mg) as anoil.

B. In a similar manner, other compounds of formula (O) were prepared.

PREPARATION 9 Compounds of Formula (R) and Formula (S)

A. 1-Benzyl-3-piperidinone (2.07 g, 10 mmol), 4-(imidazol-1-yl)aniline(1.73 g, 1.0 eq.), and Ti(OiPr)₄ (3.72 mL, 1.25 eq.) were stirred atambient temperature for 1.25 hours. The mixture was then diluted withabsolute ethanol (10 mL) and NaCNBH₃ (0.44 g, 0.67 eq.) was added. Theresulting mixture was stirred for 20 hours. Water (2 mL) was added tothe mixture with stirring and the resulting precipitate was filtered.Flash column chromatography on silical gel with 1-5% methanol inmethylene chloride gave a crude product. Further purification by HPLCafforded 3-[(4-(imidazol-1-yl)phenyl)amino]-1-benzylpiperidine (569 mg),which was dissolved in methanol (10 mL) and treated with 10% Pd/C (400mg) and ammonium formate (800 mg). The resulting mixture was heated atreflux for 4 hours. After cooling to ambient temperature, the mixturewas filtered. Evaporation of the solvent in vacuo gave3-[(4-(imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol).

B. In a similar manner, other compounds of formula (S) are prepared.

EXAMPLE 1 Compounds of Formula (I)

A. Solution A was prepared by adding(3S)-3-(4-aminophenoxy)-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (4.4g, 13.5 mmol) and NH₄OH (1.2 mL, 15 mmol) in methanol, and diluting withmethanol to 10 mL. Solution B was prepared by adding formaldehyde (1.01mL, 13.5 mmol) and 40% solution glyoxal, and then diluting with THF to10 mL. Solution A and solution B were added simultaneously to water (6.0mL, pre-heated to 65° C.) with stirring over a 30 min period. Theresulting mixture was then heated to 65° C. for 2 hours. After removalof the solvent in vacuo, the residual oil was dissolved in CH₂Cl₂ (100mL), washed with water (50 mL×3), brine (50 mL), and dried (NaSO₄).Purification by column chromatography (ethyl acetate/methanol 100:1)afforded(3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine(3.7 g, 72.5% yield), NMR: (DMSO-d6) 9.1 (s, 1), 7.90 (t, 1), 7.65-7.62(m, 2), 7.56 t, 1), 7.32 (d, 1), 7.24-7.21 (m, 2), 7.10 (d, 1), 6.98 (d,1), 5.98 (d, 2), 5.00 (m, 1), 4.28 (d, 1), 4.18 (d, 1), 3.40 (d, 1),3.12 (m, 1), 3.09-2.98 (m, 2), 2.05-1.88 (m, 3), 1.72 (m, 1) ppm.

B. In a similar manner, the following compounds of formula (I) wereprepared:

-   -   (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,        ¹H NMR (CDCl₃) 7.77 (s, 1), 7.28-7.22 (m, 3), 7.18 (d, 1), 6.96        (d, 2), 6.82 (s, 1), 6.72 (s, 2), 5.93 (s, 2), 4.38 (m, 1), 3.47        (s, 2), 3.01 (d, 1), 2.70 (m, 1), 2.20-2.02 (m, 3), 1.84-1.40        (m, 3) ppm.

C. In a similar manner, other compounds of formula (I) are prepared.

EXAMPLE 2 Compounds of Formula (II)

A. A mixture of 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]piperidine (220mg), 5-chloromethyl-1,3-benzodioxole (0.26 mL), K₂CO₃ (1.0 g), and Nal(0.1 g) in DMF (15 mL) was heated at 50° C. under N₂ for 3 hours. Afterfiltration and concentration in vacuo, the residual oil was dissolved inCH₂Cl₂ (100 mL), washed with water (20 mL×3) and brine, dried (MgSO₄),and concentrated. Purification by column chromatography gave3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,(77 mg) as a white solid, NMR: (CDCl₃) 8.30 (s, 1), 7.68 (s, 1), 7.52(d, 1), 7.22 (s, 1), 7.16 (d, 1), 6.75 (s, 2), 5.90 (d, 2), 5.41 (m, 1),3.46 (Abq, 2), 2.88 (d, 1), 2.58-2.48 (m, 2), 2.32 (m, 1), 2.10 (m, 1),1.70-1.60 (m, 2) ppm.

B. In a similar manner, the following compound of formula (II) wasprepared:

-   -   2-[((6-(imidazol-1-yl)pyridazin-3-yl)oxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,        ¹H NMR (CDCl₃) 8.28 (s, 1), 7.68 (s, 1), 7.52 (d, 2), 7.24 (s,        1), 7.19 (d, 2), 6.93 (s, 1), 6.76-6.68 (m, 2), 5.90 (s, 2),        4.70 (d, 2), 3.98 (d, 1), 3.37 (d, 1), 2.80 (m, 2), 2.18 (m, 1),        1.84-1.38 (m, 5) ppm.

C. In a similar manner, other compounds of formula (II) are prepared.

EXAMPLE 3 Compounds of Formula (I)

A. (3R)-3-[4-(Imidazol-1-yl)phenoxy]piperidine (150 mg, 0.61 mmol) wasdissolved in DMF (2 mL) and was added to a solution of5-chloromethyl-1,3-benzodioxole (0.16 ml in 50% methylene chloride, 1.0eq.) in DMF, followed by the addition of K₂CO₃ (2.5 eq.) and Nal (0.1eq.). The resulting mixture was heated at 50° C. for 1 hour. The solventwas evaporated and flash column chromatography on silical gel with 3%methanol in methylene chloride gave a crude product (112 mg). Additionalflash chromatography with 3% methanol in ethyl acetate afforded(3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methylpiperidine(70 mg), ¹H NMR (CDCl₃) 7.75 (s, 1), 7.30 (d, 2), 7.20 (d, 2), 7.00 (d,2), 6.85 (s, 1), 6.75 (d, 2), 5.90 (s, 2), 4.40 (m, 1), 3.50 (s, 2),3.00 (m, 1), 2.70 (m, 1), 2.20 (m, 3), 1.85 (m, 1), 1.50 (m, 2) ppm.

B. In a similar manner, the following compounds of formula (I) wereprepared:

-   -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,        trifluoroacetic acid salt, ¹H NMR (DMSO-d₆) 9.60 (m, 1), 8.20        (m, 1), 7.90 ( s, 1), 7.70 ( m, 2), 7.20 (m, 3), 7.00 (m, 2),        6.00 (s, 2), 4.50 (m, 1), 4.30 (m, 2), 4.00 (m, 1), 3.30 (m, 2),        3.00 (m, 1), 2.30 (m, 1), 1.70-2.00 (m, 3) ppm;    -   (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,        ¹H NMR(DMSO-d₆) 9.60 (m, 1), 8.20 (m, 1), 7.90 (s, 1), 7.70 (m,        2), 7.00-7.30 (m, 5), 6.0 (s, 2), 4.50 (m, 1), 4.30 (m, 2), 4.00        (m, 1), 3.20-3.40 ( m, 2), 3.00 (m, 1), 2.30 (m, 1), 1.70-2.00        (m, 3) ppm;    -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,        ¹H NMR(CDCl₃) 7.74 (s, 1), 7.25 (d, 2), 7.16 (s, 2), 6.94 (d,        2), 6.82 (s, 1), 6.71 (s, 2), 5.90 (s, 2), 4.35 (m, 1), 3.45 (AB        q, 2), 3.00 (m, 1), 2.70 (m, 1), 2.10-2.38 (m, 3), 1.45 (m, 2)        ppm;    -   3-[4-(imidazol-1-yl)phenoxy]-1-(3,4-dimethoxybenzyl)piperidine,        ¹H NMR(CDCl₃) 7.80 (s, 1), 7.30 (m, 3), 7.20 (d, 2), 7.00 (d,        2), 6.80 (m, 2), 4.40 (m, 1), 3.90 (s, 6), 3.50 (AB q, 2), 3.00        (m, 1), 2.70 (m, 1), 2.10-2.30 (m, 3), 1.80 (m, 2), 1.50 (m, 2)        ppm;    -   3-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methylpiperidine,        ¹H NMR(CDCl₃) 7.80 (s, 1), 7.30 (d, 2), 7.20 (d, 2), 6.95 (d,        2), 6.85 (s, 1), 6.75 (s, 2), 5.95 (s, 2), 3.80 (d, 2), 3.40 (AB        q, 2), 2.90 (m, 1), 2,70 (m, 1), 2.20 (m, 1), 1.70 (m, 3), 1.20        (m, 1) ppm;    -   2-[(4-(imidazol-1-yl)phenoxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine,        ¹H NMR(CDCl₃) 7.75 (s, 1), 7.30 (d, 2), 7.20 (d, 2), 7.00 (d,        2), 6.90 (s, 1), 6.70 (m, 2), 5.90 (s, 2), 4.20 (m, 1), 4.00 (m,        2), 3.36 (m, 1), 2,80 (m, 1), 2.20 (m, 1), 1.40-1.90 (m, 6) ppm;    -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]hexahydro-1H-azepine,        ¹H NMR(CDCl₃) 7.70 (s, 1), 7.10 (m, 4), 6.90 (s, 1), 6.60-6.80        (m, 4), 5.90 (s, 2), 4.30 (m, 1), 3.50 (AB q, 2), 2.80 (m, 2),        2.60 ( m, 2), 2.10 (m, 1), 1.60-1.80 (m, 5) ppm;    -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)carbonyl]pyrrolidine,        ¹H NMR (CDCl₃) 7.63 (s, 1), 7.22-6.80 (m, 8), 6.66 (d, 1), 5.82        (s, 2), 4.86 (m, 1), 3.90-3.50 (m, 4), 2.18-2.05 (m, 2) ppm;    -   (3S)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine,        ¹H NMR (CDCl₃) 7.74 (s, 1), 7.24-7.22 (m, 3), 7.16 (d, 2), 6.88        (d, 2), 6.83 (s, 1), 6.76-6.73 (m, 2), 5.92 (s, 2), 4.80 (m, 1),        3.95 (d, 1), 3.54 (d, 1), 2.92 (m, 1), 2.78-2.68 (m, 2), 2.58        (m, 1), 2.15 (m, 1), 1.98 (m, 1) ppm; and    -   3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]pyrrolidine,        ¹H NMR (CDCl₃) 7.62 (s, 1), 7.17 (d, 2), 7.08 (d, 2), 6.81-6.78        (m, 3), 6.68-6.61 (m, 2), 5.80 (s, 2), 4.73 (m, 1), 3.48 (AB q,        2), 2.84 (m, 1), 2.70-2.62 (m,2), 2.48 (m, 1), 2.21 (m, 1), 1.88        (m, 1) ppm.

C. In a similar manner, other compounds of formula (I) are prepared.

EXAMPLE 4 Compounds of Formula (I)

A. 3-[(4-(Imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol) wasdissolved in DMF and then treated with 5-chloromethyl-1,3-benzodioxole(1.0 eq.), K₂CO₃ (2.5 eq.) and Nal (0.1 eq.). The resulting mixture washeated at 50° C. for 1 hour. Filtration of the mixture and evaporationof the solvent in vacuo gave a crude product (411 mg). Flash columnchromatography on silical gel with 1-2.5% methanol in methylene chlorideafforded3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine(110 mg), ¹H NMR(CDCl₃) 7.70 (s, 1), 7.10 (m, 4), 6.80 (s, 1), 6.70 (m,2), 6.60 (d, 2), 5.90 (s, 2), 4.30 (m, 1), 3.60 (m, 1), 3.40 (AB q, 2),2.70 (m, 1), 2.40 (m, 3), 1.50-1.80 (m, 4) ppm.

B. In a similar manner, other compounds of formula (I) are prepared.

EXAMPLE 5 Compounds of Formula (I)

A. To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq,298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). Theresulting mixture was stirred overnight. The methanol was evaporated,and the residue diluted with ethyl acetate, washed with water and brine.Evaporation of the solvent in vacuo gave a crude product. Flash columnchromatography on silical gel with 1-2% methanol in methylene chlorideafforded3-[4-(imidazol-1-yl)phenoxy]-1-[(4-methoxynaphth-1-yl)methyl]piperidine(54 mg), ¹H NMR(CDCl₃) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s,1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3),3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10-2.30 (m, 3), 1.80 (m,1), 1.40-1.70 (m, 2) ppm.

B. In a similar manner, other compounds of formula (I) are prepared.

EXAMPLE 6 Compound of Formula (III)

A. To 2-[4-(imidazol-1-yl)phenoxy]ethylamine (4.0 g, 20 mmol) dissolvedin MeOH (150 mL) was added piperonal (3.0 g, 20 mmol) and acetic acid(1.5 mL). After stirring for 1 h, NaBH₃CN (2.6 g, 40 mmol) was added.After stirring for 18 hour, the solvent was removed in vacuo and theresidue was chromatographed on silical gel with 2% methanol in methylenechloride to give 3.5 g ofN-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine,¹H NMR (DMSO-d₆) 8.12 (s, 1), 7.62 (s, 1), 7.54 (d, 2), 7.08-7.02 (m,3), 6.90 (s, 1), 6.82-6.75 (m, 2), 5.94 (s, 2), 4.03 (t, 2), 3.62 (s,2), 3.32 (s, 1), 2.80 (t, 2) ppm.

B. In a similar manner, the following compounds of formula (III) wereprepared:

-   -   N-(carboxymethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-(ethoxycarbonylmethyl)-N-[2-4-imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N,N-di[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-[(((3-(2-methylpiperidin-1-yl)propyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-[((((1,3-benzodioxol-5-yl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;    -   N-[((((4-trifluoromethylphenyl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;        and    -   N-[(((butyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine.

EXAMPLE 7

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof: A. Ingredients % wt./wt. Compound of the invention 20.0%Lactose 79.5% Magnesium stearate 0.5%

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each, one capsule would approximate a totaldaily dosage. B. Ingredients % wt./wt. Compound of the invention 20.0%Magnesium stearate 0.9% Starch 8.6% Lactose 69.6% PVP(polyvinylpyrrolidine) 0.9%

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine. C. IngredientsCompound of the invention 0.1 g Propylene glycol 20.0 g Polyethyleneglycol 400 20.0 g Polysorbate 80 1.0 g Water q.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled. D. Ingredients % wt./wt. Compound of theinvention 20.0% Peanut Oil 78.0% Span 60 2.0%

The above ingredients are melted, mixed and filled into soft elasticcapsules. E. Ingredients % wt./wt. Compound of the invention 1.0% Methylor carboxymethyl cellulose 2.0% 0.9% saline q.s. 100 mL

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 8

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof: Ingredients Compound of the invention 0.02 g Propylene glycol20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g 0.9% Salinesolution q.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 m membrane filter andpackaged under sterile conditions.

EXAMPLE 9

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof:Ingredients % wt./wt. Compound of the invention 1.0% Polyethylene glycol1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 10

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof: Ingredients %wt./wt. Micronized compound of the invention 1.0% Micronized lactose99.0%

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 11

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof:Ingredients % wt./wt. Compound of the invention 0.005% Water 89.995%Ethanol 10.000%

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 12

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt-thereof: Ingredients %Wt./Wt. Compound of the invention 0.10% Propellant 11/12 98.90% Oleicacid 1.00%

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 13 (In Vitro Assay)

Induction of iNOS in RAW 264.7 Mouse Monocytes

RAW 264.7 murine macrophage cells were obtained from American TypeCulture Collection (Rockville, Md.) and were maintained in RPMI 1640containing 10% fetal bovine serum (FBS), 5000 units/mL of penicillin andstreptomycin, and 2 mM glutamine (maintenance medium). NOS activity wasmeasured by a fluorescent assay of the nitric oxide oxidation product,nitrite (Diamani et al., Talanta (1986), Vol. 33, pp. 649-652).Induction of iNOS (inducible nitric oxide synthase) is stimulated bytreatment of the cells with lipopolysaccharide and γ-interferon. Theassay is described in more detail below.

Cells were harvested, diluted to 500,000 cells/mL with maintenancemedium, and seeded into 96-well plates at 100 μL/well. The plates wereincubated overnight at 37° C., under a 5% CO₂ atmosphere. The medium wasthen replaced with 90 μL of BME medium containing 10% FBS, 100 units/mLof penicillin, 100 μL streptomycin, 2 mM glutamine, 100 units/mL ofγ-interferon and 2 μg/mL of lipopolysaccharide.N-guanidino-methyl-L-arginine was added to four wells (negative control)at a final concentration of 200 μM using 10 μL of 2 mM stock solution in100 mM Hepes, pH 7.3+0.1% DMSO and four wells received only the 100 mMHepes/0.1% DMSO buffer (positive control). Compounds of the inventionwere dissolved at 10-fold the desired final concentration in Hepes/DMSOand 10 μL of these solutions was transferred to the 96-well plate. Theplates were incubated for 17 hrs at 37° C., under a 5% CO₂ atmosphere.Nitrite accumulation in the culture medium was determined as follows: Toeach well was added 15 μL of 2,3-diaminonaphthalene (10 :g/mL in 0.75 MHCl) and each well was then incubated for 10 minutes at roomtemperature. To each well was then added 15 μL of 1 N NaOH and thefluorescence emission was measured at 405 nm, using an excitationwavelength of 365 nm. Enzyme activity in the experimental wells wasnormalized to percent control using the positive and negative controlvalues. The signal to noise ratio was >10 for the assay.

The compounds of the invention, when tested in this assay, demonstratedthe ability to inhibit nitric oxide production in vitro.

EXAMPLE 14 (In Vitro Assay)

A. A172 cells were obtained from the American Type Culture Collection,and were cultured routinely in DMEM without phenol red or sodiumpyruvate but containing high glucose (Gibco BRL), supplemented with 10%(v/v) fetal bovine serum (Gibco BRL), in a humidified atmosphere of 5%CO₂ in air at 37° C. Cells were harvested and plated at 100,000cells/well into 96-well tissue culture dishes in a total of 100 μL ofculture medium. 18-24 hours later, inducible nitric oxide synthase(iNOS) activity was induced by the addition of 222 U/ml humaninterferon-gamma, 22 ng/ml of human tumor necrosis factor-alpha, and 2.2ng/mL of human interleukin 1-β. All cytokines were purchased fromBoehringer Mannheim. Concomitant with cytokine addition, the appropriateconcentration of the compound of the invention was also added. Compoundstock solutions were prepared in DMSO, and vehicle was added to controlwells. Final concentration of DMSO in the incubations was less than0.2%, and had no influence on iNOS induction or activity measurements.Incubations were continued for 18-24 hours, at which time an aliquot ofthe culture medium was removed and tested for nitrite concentrationusing the Griess reagent (see below).

B. Following incubation with cytokines plus compound, a 100 μL aliquotof the culture medium was removed and mixed with 150 μL of the Griessreagent (5% v/v phosphoric acid containing 2% w/v sulfanilamide plus0.2% w/v naphthylethylenediamine) in a separate 96-well plate. Theplates were read within 15 min at 550 nm in a SpectraMaxspectrophotometer. The inhibition of iNOS activity by compound resultedin a decrease in the OD550 of the medium. IC₅₀ values were calculatedfrom a log-logit analysis of the data. Inhibition curves with Hillslopes of less than 0.5 or greater than 1.5 were rejected.

Control experiments showed that no significant conversion of nitrite tonitrate occurred over the course of an experiment. Cells incubated inthe absence of cytokines produced no measurable nitrite. Therefore,measuring the nitrite content of the culture medium of cytokine-inducedcells is a simple, accurate means of measuring the induction of iNOSactivity in these cells.

Compounds of the invention, when tested in this assay, demonstrated theability to inhibit nitric oxide production in vitro.

EXAMPLE 15 (In Vivo Assay)

Effects of Compounds of the Invention on Adjuvant-Induced Arthritis inRats

Male Lewis rats are injected intradermally (proximal quarter of thetail) with 0.1 mL of Mycobacterium butyricum in Incomplete Freund'sAdjuvant (10 mg/mL). Either the vehicle (acidified saline, 1 mL/kg) or acompound of the invention (3, 10, or 30 mg/kg) is administeredsubcutaneously (b.i.d.), starting on the day following adjuvantimmunization, and continued until the end of the experiment (N=10 ratsper treatment group). Clinical scores (see below) are measured in alllimbs 3 times per week throughout the study. Rats are euthanized 34-35days after immunization. At the time of euthanasia, a radiologicevaluation (see below) of the hind paws is performed, a blood sample iscollected for clinical blood chemistry and drug levels (high dose grouponly; 6 or 12 hours post final dose), a section of liver is obtained formeasurement of potential toxicity, and the hind limbs are preserved forhistopathological determination.

Clinical scoring—each limb is graded according to the following scale: 0no signs of inflammation 1 moderate redness, first indication ofswelling, joint flexible 2 moderate redness, moderate swelling, jointflexible 3 redness, significant swelling and distortion of the paw,joint beginning to fuse 4 redness, gross swelling and distortion of thepaw, joint completely fused

Radiological scoring—each hind limb is graded on a scale of 0-3 for eachof the following parameters:

-   -   soft tissue swelling    -   cartilage loss    -   erosion    -   heterotropic ossification

The compounds of the invention, when tested in this assay, demonstratethe ability to treat the arthritis present in the rats.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound selected from the group consisting of the followingformulae:

wherein: each n is 0 to 2; each m is 0 to 4; each p is 0 to 2; A¹ is—O—(CH₂)_(q)— (where q is 0 to 3), —(CH₂)_(q)—O— (where q is 0 to 3),—N(R⁶)—(CH₂)_(q)— (wherein q is 0 to 3) or —(CH₂)_(q)—N(R⁶)— (where q is0 to 3); A² is —(CH₂)_(q)—O— (where q is 2 to 3); R¹ is hydrogen, alkyl,—(CH₂)_(t)—C(O)OR⁷ (where t is 0 to 6), —(CH₂)_(t)—C(O)N(R⁶)R⁷ (where tis 0 to 6), or —C(O)R⁷; or R¹ is aralkyl (where the aryl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR² is independently halo, haloalkyl, alkyl, nitro, —OR⁶, —C(O)OR⁶,—C(O)N(R⁶)R⁷, —N(R⁶)R⁷, —N(R⁶)C(O)R⁷, or —N(H)S(O)₂R⁸; each R³ isindependently hydrogen or alkyl; each R⁴ is independently alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; R⁵ ishydrogen, alkyl, aralkyl, —(CH₂)_(m)—C(O)—OR⁹ (where m is 1 to 4),—(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or heterocyclylalkyl(where the heterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR⁵ and R⁷ is independently hydrogen, alkyl, aryl (optionally substitutedby one or more substituents selected from the group consisting of halo,alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl (wherein thearyl is optionally substituted by one or more substituents selected fromthe group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl), heterocyclyl (optionally substituted by one ormore substituents selected from the group consisting of halo, alkyl,aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl), or heterocyclylalkyl(wherein the heterocyclyl radical is optionally substituted by one ormore substituents selected from the group consisting of halo, alkyl,aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl); and each R⁸ is alkyl,aryl (optionally substituted by one or more substituents selected fromthe group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl), or aralkyl (wherein the aryl is optionallysubstituted by one or more substituents selected from the groupconsisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR⁹ is independently hydrogen, alkyl or aralkyl (where the aryl radicalis optionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); and R¹⁰ is hydrogen, alkyl, or aralkyl (where thearyl radical is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, hydroxy,alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,and dialkylaminocarbonyl); or R¹⁰ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); as asingle stereoisomer, a mixture of stereoisomers, or as a racemic mixtureof stereoisomers; or a pharmaceutically acceptable salt thereof. 2-15.(canceled)
 16. The compound of claim 1 selected from formula (II):


17. The compound of claim 16 wherein: n and p are each independently 0to 2; A¹ is —O—(CH₂)_(q)— (where q is 0 to 1), —(CH₂)_(q)—O— (where q is0 to 1), —N(R⁶)—(CH₂)_(q)— (where q is 0 to 1) or —(CH₂)_(q)—N(R⁶)—(where q is 0 to 1); R¹ is (1,3-benzodioxol-5-yl)alkyl (where thebenzodioxolyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); R² is halo, haloalkyl, alkyl, nitro, —OR⁶,—C(O)OR⁶, —C(O)N(R⁶)R⁷, or —N(R⁶)R⁷; each R³ is independently hydrogenor alkyl; each R⁴ is independently alkyl, halo, haloalkyl, hydroxy,alkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl; and each R⁶ and R⁷ is independently hydrogen oralkyl.
 18. The compound of claim 17 wherein: n and p are eachindependently 0 to 2; A¹ is —O—, —CH₂—O—, or —N(R⁶)—; R¹ is(1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, hydroxy, and alkoxy); R² is halo, haloalkyl,alkyl, or —OR⁶; each R³ is independently hydrogen or alkyl; each R⁴ isindependently alkyl, halo, haloalkyl, hydroxy, alkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R⁶is hydrogen or alkyl.
 19. The compound of claim 18 wherein: n is 0 to 2;p is 0 to 2; A¹ is —O— or —CH₂O—; R¹ is (1,3-benzodioxol-5-yl)alkyl(where the benzodioxolyl radical is optionally substituted by one ormore substituents selected from the group consisting of alkyl, hydroxy,and alkoxy); R² is halo, haloalkyl, alkyl, or —OR⁶; R³ is hydrogen oralkyl; each R⁴ is independently alkyl, halo, haloalkyl, hydroxy, alkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; and R⁶is hydrogen or alkyl.
 20. The compound of claim 19 selected from thegroup consisting of the following compounds:3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine;and2-[((6-(imidazol-1-yl)pyridazin-3-yl)oxy)methyl]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine.21. The compound of claim 1 selected from formula (III):


22. The compound of claim 21 wherein: m is 0 to 4; A² is —(CH₂)_(q)—O—(where q is 2 to 3); R¹ is aralkyl (where the aryl radical is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R¹is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR² is independently halo, haloalkyl, alkyl, —OR⁶, —C(O)OR⁶,—C(O)N(R⁶)R⁷, —N(R⁶)R⁷, or —N(R⁶)C(O)R⁷; R³ is independently hydrogen oralkyl; R⁵ is hydrogen, alkyl, aralkyl, —(CH₂)_(m)—C(O)—OR⁹ (where m is 1to 4), —(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or(1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); each R⁶ and R⁷ is independently hydrogen oralkyl; each R⁹ is independently hydrogen or alkyl; and R¹⁰ is hydrogen,alkyl, aralkyl (where the aryl radical is optionally substituted by oneor more substituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R¹⁰is (1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹⁰ is N-heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl). 23.The compound of claim 22 wherein: m is 0; A² is —CH₂—CH₂—O—; R¹ is(1,3-benzodioxol-5-yl)alkyl (where the benzodioxolyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); R³ ishydrogen; R⁵ is hydrogen, —(CH₂)_(m)—C(O)—OR⁹ (where m is 1 to 4),—(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or(1,3-benzodioxol-5-yl)alkyl; each R⁹ is independently hydrogen or alkyl;and R¹⁰ is hydrogen, alkyl, aralkyl (where the aryl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹⁰ is (1,3-benzodioxol-5-yl)alkyl (where thebenzodioxolyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); or R¹⁰is N-heterocyclylalkyl (where the heterocyclyl radical is optionallysubstituted by by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy, aryl,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl).
 24. The compound of claim 23 wherein: R¹ is(1,3-benzodioxol-5-yl)methyl; R⁵ is hydrogen, —CH₂—C(O)—OR⁹,—CH₂—C(O)—N(R⁹)R¹⁰, or (1,3-benzodioxol-5-yl)methyl; each R⁹ isindependently hydrogen or alkyl; and R¹⁰ is hydrogen, alkyl, aralkyl(where the aryl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹⁰ is (1,3-benzodioxol-5-yl)methyl; and orR¹⁰ is piperidin-1-ylalkyl (wherein the piperidinyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl).
 25. The compound of claim 24 wherein: R⁵ ishydrogen or —CH₂—C(O)—OR⁹; and R⁹ is hydrogen or alkyl.
 26. The compoundof claim 25 selected from the group consisting of the followingcompounds:N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;N-(carboxymethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;andN-(ethoxycarbonylmethyl)-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine.27. The compound of claim 24 wherein R⁵ is (1,3-benzodioxol-5-yl)methyl,namely,N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N,N-di[(1,3-benzodioxol-5-yl)methyl]amine.28. The compound of claim 24 wherein: R⁵ is —CH₂—C(O)—N(R⁹)R¹⁰; R⁹ isindependently hydrogen or alkyl; and R¹⁰ is hydrogen, alkyl, aralkyl(where the aryl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, amino, dialkylamino, monoalkylamino,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹⁰ is (1,3-benzodioxol-5-yl)methyl; and orR¹⁰ is piperidin-1-ylalkyl (wherein the piperidinyl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl).
 29. The compound of claim 28 selected from thegroup consisting of the following compounds:N-[(((3-(2-methylpiperidin-1-yl)propyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;N-[((((1,3-benzodioxo-5-yl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;N-[((((4-trifluoromethylphenyl)methyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine;and N-[(((butyl)amino)carbonyl)methyl]-N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine.
 30. Apharmaceutical composition useful in treating a condition in a mammalresulting from an abnormality in nitric oxide production, whichcomposition comprises a pharmaceutically excipient excipient and atherapeutically effective amount of a compound selected from the groupconsisting of the following formulae:

wherein: each n is 0 to 2; each m is 0 to 4; each p is 0 to 2; A¹ is—O—(CH₂)_(q)— (where q is 0 to 3), —(CH₂)_(q)—O— (where q is 0 to 3),—N(R⁶)—(CH₂)_(q)— (where q is 0 to 3) or —(CH₂)_(q)—N(R⁶)— (where q is 0to 3); A² is —(CH₂)_(q)—O— (where q is 2 to 3); R¹ is hydrogen, alkyl,—C(O)N(R⁶)R⁷, or —C(O)R⁷; or R¹ is aralkyl (where the aryl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR² is independently halo, haloalkyl, alkyl, nitro, —OR⁶, —C(O)OR⁶,—C(O)N(R⁶)R⁷, —N(R⁶)R⁷, —N(R⁶)C(O)R⁷, or —N(H)S(O)₂R⁸; each R³ isindependently hydrogen or alkyl; each R⁴ is independently alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; R⁵ ishydrogen, alkyl, aralkyl, —(CH₂)_(m)—C(O)—OR⁹ (where m is 1 to 4),—(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or heterocyclylalkyl(where the heterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR⁶ and R⁷ is independently hydrogen, alkyl, aryl (optionally substitutedby one or more substituents selected from the group consisting of halo,alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl (wherein thearyl is optionally substituted by one or more substituents selected fromthe group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl), heterocyclyl (optionally substituted by one ormore substituents selected from the group consisting of halo, alkyl,aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl), or heterocyclylalkyl(wherein the heterocyclyl radical is optionally substituted by one ormore substituents selected from the group consisting of halo, alkyl,aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl); and each R⁸ is alkyl,aryl (optionally substituted by one or more substituents selected fromthe group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl), or aralkyl (wherein the aryl is optionallysubstituted by one or more substituents selected from the groupconsisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR⁹ is independently hydrogen, alkyl or aralkyl (where the aryl radicalis optionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); and R¹⁰ is hydrogen, alkyl, or aralkyl (where thearyl radical is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, hydroxy,alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,and dialkylaminocarbonyl); or R¹⁰ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); as asingle stereoisomer, a mixture of stereoisomers, or as a racemic mixtureof stereoisomers; or a pharmaceutically acceptable salt thereof.
 31. Amethod of treating a condition in a mammal resulting from an abnormalityin nitric oxide production which comprises administering to a mammalhaving a condition resulting from an abnormality in nitric oxideproduction a therapeutically effective amount of a compound selectedfrom the group consisting of the following formulae:

wherein: each n is 0 to 2; each m is 0 to 4; each p is 0 to 2; A¹ is—O—(CH₂)_(q)— (where q is 0 to 3), —(CH₂)_(q)—O— (where q is 0 to 3),—N(R⁶)—(CH₂)_(q)— (where q is 0 to 3) or —(CH₂)_(q)—N(R⁶)— (where q is 0to 3); A² is —(CH₂)_(q)—O— (where q is 2 to 3); R¹ is hydrogen, alkyl,—C(O)N(R6)R⁷, or —C(O)R⁷; or R¹ is aralkyl (where the aryl radical isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); or R¹ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR² is independently halo, haloalkyl, alkyl, nitro, —OR⁶, —C(O)OR⁶,—C(O)N(R⁶)R⁷, —N(R⁶)R⁷, —N(R⁶)C(O)R⁷, or —N(H)S(O)₂R⁸; each R³ isindependently hydrogen or alkyl; each R⁴ is independently alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; R⁵ ishydrogen, alkyl, aralkyl, —(CH₂)_(m)—C(O)—OR⁹ (where m is 1 to 4),—(CH₂)_(m)—C(O)—N(R⁹)R¹⁰ (where m is 1 to 4), or heterocyclylalkyl(where the heterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR⁶ and R⁷ is independently hydrogen, alkyl, aryl (optionally substitutedby one or more substituents selected from the group consisting of halo,alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl), aralkyl (wherein thearyl is optionally substituted by one or more substituents selected fromthe group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl), heterocyclyl (optionally substituted by one ormore substituents selected from the group consisting of halo, alkyl,aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl), or heterocyclylalkyl(wherein the heterocyclyl radical is optionally substituted by one ormore substituents selected from the group consisting of halo, alkyl,aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl); and each R⁸ is alkyl,aryl (optionally substituted by one or more substituents selected fromthe group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl), or aralkyl (wherein the aryl is optionallysubstituted by one or more substituents selected from the groupconsisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); eachR⁹ is independently hydrogen, alkyl or aralkyl (where the aryl radicalis optionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxy, alkoxy, aralkoxy,aryl, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl); and R¹⁰ is hydrogen, alkyl, or aralkyl (where thearyl radical is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, hydroxy,alkoxy, aralkoxy, aryl, aralkyl, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,and dialkylaminocarbonyl); or R¹⁰ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, hydroxy, alkoxy, aralkoxy, aryl, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl); as asingle stereoisomer, a mixture of stereoisomers, or as a racemic mixtureof stereoisomers; or a pharmaceutically acceptable salt thereof.
 32. Themethod according to claim 31 wherein said condition resulting from anabnormality in nitric oxide production is chosen from the groupconsisting of multiple sclerosis, stroke or cerebral ischemia,Alzheimer's disease, HIV dementia, Parkinson's disease, meningitis,dilated cardiomyopathy and congestive heart failure, atherosclerosis,restenosis or graft stenosis, septic shock and hypotension, hemorrhagicshock, asthma, acute respiratory distress syndrome, smoke orparticulate-mediated lung injury, pathogen-mediated pneumonias, traumaof various etiologies, rheumatoid arthritis and osteoarthritis,glomerulonephritis, systemic lupus erythematosus, inflammatory boweldiseases such as ulcerative colitis and Crohn's disease, insulindependent diabetes mellitus, diabetic neuropathy or nephropathy, acuteand chronic organ transplant rejection, transplant vasculopathies,graft-versus-host disease, psoriasis and other inflammatory skindiseases, and cancer.
 33. The method of claim 32 wherein the conditionis multiple sclerosis.
 34. The method of claim 32 wherein the conditionis rheumatoid arthritis.
 35. The method of claim 32 wherein thecondition is dilated cardiomyopathy.
 36. The method of claim 32 whereinthe condition is congestive heart failure.